Abstract: Lung cancer is the number one cause of cancer death in both men and women in the United States. In fact, more deaths will occur this year from lung cancer than breast, prostate, and colorectal cancers combined. Lung cancer has been identified as a medical priority for the Department of Veterans affairs due to the high rates of tobacco addiction acquired by military personnel. The cumulative five-year survival rate for lung cancer remains approximately 15%, thus improved success in decreasing death from lung cancer will rely not only on smoking prevention and cessation, but the future development of molecular therapeutic targets for treatment. The Wnt signaling pathway, is a highly conserved signaling pathway that is critical for normal development and mutation of specific components has been implicated in many human cancers including colon, breast, and melanoma, but has yet to be fully examined in detail in lung cancers. The overall goal of this study is to determine the role of Fzd 9 (2-catenin independent) signaling on the initiation and promotion of NSCLC. Our findings to date suggest two seemingly unrelated Fzd 9 functions: 1) that Fzd 9 participates in acting as a tumor suppressor in normal lung epithelia, and 2) that activation of Fzd 9 activates 2-catenin independent (non-canonical) Wnt signaling through its interactions with both the Wnt 7a and prostacyclin pathways, inducing activation of the tumor suppressor gene PPAR3. In previous work, we have demonstrated that Wnt 7a and/or Fzd 9 expression is frequently reduced in NSCLC, and that the loss of Wnt 7a and/or Fzd 9 is strongly associated with epithelial to mesenchymal transition (EMT), loss of cellular polarity, and increased susceptibility to lung carcinogensis in mice. In addition, we have also discovered that prostacyclin and its synthetic analog iloprost are able to mimic many of the effects of Wnt 7a. We hypothesize that Fzd 9 is part of an important tumor suppressor gene pathway, and it's lost will lead to increased EMT and/or transformation in non-transformed lung cultured cell lines. In addition, we have previously demonstrated that with restoration of Fzd 9 in NSCLC we could reverse the transformed phenotype, by inducing a number of downstream tumor suppressor targets. Thus we hypothesize that loss of Fzd 9 in normal lung will result in decreased signaling of the tumor suppressive effects. Lastly, we also hypothesize that the mechanism by which iloprost/Fzd 9 inhibits NSCLC cell growth is similar to that of the Wnt 7a/Fzd 9 PUBLIC HEALTH RELEVANCE: Investigations into molecular cancer therapy of lung cancer are directly relevant to the Department of Veterans'Affairs patient care mission, as lung cancer is a Veterans'Affairs medical research priority. Lung cancer is the leading cause of cancer death in the veteran population. While tobacco abuse is currently discouraged by the military, there still exists a very large percentage of high-risk current and former smokers cared for by the VA that might benefit from advances in therapeutic molecular targeting in lung cancer. Agent Orange and asbestos exposure, well-established lung carcinogens, are service-connected disorders and have strongly been associated with lung cancer. Research investigating the mechanisms and strategies for lung cancer molecular therapeutic therapy has tremendous potential benefit to veterans, many of whom no longer smoke, yet remain at high risk for lung cancer.